1. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 1 |1 | The need for Pharmacovigilance Shanthi Pal Quality Assurance and Safety of Medicines

2. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 2 |2 | What is Pharmacovigilance? WHO definition: The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. This applies throughout the life cycle of a medicine equally to the pre-approval stage as to the post-approval.

3. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 3 |3 | Why do we need pharmacovigilance? Will PV prevent these?

4. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 4 |4 | Risk No medicinal product is entirely or absolutely safe for all people, in all places, at all times. We must always live with some measure of uncertainty. PV can characterise that risk

5. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 5 |5 | W hy do we need pharmacovigilance? Ten reasons why….

6. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 6 |6 | Why do we need pharmacovigilance? Reason 1: Insufficient evidence of safety from clinical trials

7. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 7 |7 | Drug Development

8. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 8 |8 | Rule of 3 There is 95% chance of observing one occurence of an event in a population 3 times the size of the event’s frequency –e.g. if the incidence is 1 / 10 000 –30 000 patients to find one case

9. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 9 |9 | 'other' limitations of phase 1 -3 clinical trials narrow population: age and sex specific narrow indications: only the specific disease studied short duration: often no longer than a few weeks

10. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 10 | Reason 2 Medicines are supposed to save lives Dying from a disease is sometimes unavoidable; dying from a medicine is unacceptable. Lepakhin V. Geneva 2005

11. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 11 | UK: US: ADRs were 4 th -6 th commonest cause of death in the US in 1994 Lazarou et al, 1998 It has been suggested that ADRs may cause 5700 deaths per year in UK. Pirmohamed et al, 2004

12. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 12 | Reason 3 To KEEP products on the market

13. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 13 | Examples of product recalls due to toxicity MedicineYear Thalidomide1965 Practolol1975 Clioquinol1970 Benoxaprofen1982 Terfenadine1997 Rofecoxib2004 Veralipride2007 Examples of serious and unexpected adverse events leading to withdrawal of medicine Phocomelia Sclerosing peritonitis Subacute nephropathy Nephrotoxicity, cholestatic jaundice Torsade de pointes Cardiovascular effects Anxiety, depression, movement disorders

14. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 14 | But… Is product recall the aim of PV?

15. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 15 | No because... No drug is inherently safe –unless it has no effect at all! Each patient is unique Each treatment situation is unique –What is the right drug for me might be a bad choice for you Understanding this will help make the right choice for each patient if patients do well, so will the drugs (but not necessarily the other way around!)

16. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 16 | Reason 4 To protect patients from unnecessary harm Many ADRs are preventable

17. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 17 | 125 Patients 24 Patients experienced ADRs (19%) (59%) were avoidable

18. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 18 | Burden of ADRs Mumbai, India 6.9 % of hospital admissions 0.85% fatality 60% avoidable Patel KJ et al BMC Clin Pharmacol 2007, 7:8

19. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 19 | Preventable problems

20. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 20 | Reason 5 To reduce healthcare expenses ADRs are a huge burden !!

21. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 21 | 6.5% of admissions are due to ADRs Seven 800-bed hospitals are occupied by ADR patients Cost £446 million per annum

22. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 22 | Cost of ADRs in the US? Cost of drug related morbidity and mortality exceeded $177.4 billion in 2000 (Ernst FR & Grizzle AJ, 2001: J American Pharm. Assoc) ADR related cost to the country exceeds the cost of the medications themselves

23. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 23 | More recent data from EU as a whole Cost due to ADRs in EU: € 79 billions/year Ref: Press Release from Brussels, 10 Dec 2008.

24. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 24 | Cost due to ADRs Mumbai, India Additional cost to hospital INR 6197/patient (US$150) Patel KJ et al BMC Clin Pharmacol 2007, 7:8

25. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 25 | Reason 6 Because any medicine can be implicated England NSAID Diuretics Warfarin ACE inhibitors Antidepressants Mumbai Anti-TB Antiepileptics Antimalarials Anticoagulants Oral antidiabetics

26. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 26 | Reason 7 Promoting rational use of medicines and adherence

27. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 27 | Prescription Dr A. Who 31 December 2000 Re: Mr Joseph Bloggs 1) abacavir + lamivudine + zidovudine 1 BD 2) atenolol 100 mg/d 3) acetylsalicylic acid 150mg/d 4) cerivastatin 10 mg/d 5) gemfibrozil 200 mg/d 6) metformin 500 mg/d 7) fluoxetine 50 mg/d 8) Sildenafil

28. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 28 | Main reasons of discontinuation of first HAART regimen within 1st year: ICONA ICO N A Italian Cohort Naive Antiretroviral Monforte et al. AIDS 1999

29. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 29 | Reason 8 Ensuring public confidence If something can go wrong, it will – Murphy's law

30. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 30 |

31. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 31 | Reason 9 Ethical thing to do To know of something that is harmful to another person who does not know, and not telling, is unethical

32. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 32 | Not reporting a serious unknown reaction is unethical valid for everyone patient health professional manufacturer authorities

33. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 33 | Consequence Guardian Weekly March 18-24 2004 disaster !! ALLEGATION: Known about SSRI prescribing at unsafe doses for a decade

34. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 34 | Reason 10 It can unveil lapses in BEST PRACTICES Unexpected lack of effect –counterfeiting –resistance –interaction Quality problems Dependence and abuse Poisoning Medication errors

35. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 35 | Pharmacovigilance Major Aims early detection of unknown safety problems detection of increases in frequency identification of risk factors quantifying risks communicating information preventing patients from being affected unnecessarily Rational and Safe use of Medicines

36. PV of ARVs, 23- 28 November 2009, Dar Es Salaam 36 | Pharmacovigilance is Essential